WO2007130785A2 - Matériaux et procédés de traitement de la pneumonie interstitielle à pneumocystis carinii - Google Patents

Matériaux et procédés de traitement de la pneumonie interstitielle à pneumocystis carinii Download PDF

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WO2007130785A2
WO2007130785A2 PCT/US2007/066925 US2007066925W WO2007130785A2 WO 2007130785 A2 WO2007130785 A2 WO 2007130785A2 US 2007066925 W US2007066925 W US 2007066925W WO 2007130785 A2 WO2007130785 A2 WO 2007130785A2
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pneumocystis
pneumocystis pneumonia
polypeptide
agent
pneumonia
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PCT/US2007/066925
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WO2007130785A3 (fr
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Andrea Keane-Myers
Rosanne Spolski
Warren J. Leonard
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Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/37—Assays involving biological materials from specific organisms or of a specific nature from fungi
    • G01N2333/375—Assays involving biological materials from specific organisms or of a specific nature from fungi from Basidiomycetes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/715—Assays involving receptors, cell surface antigens or cell surface determinants for cytokines; for lymphokines; for interferons
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases

Definitions

  • Pneumocystis pneumonia is a rare opportunistic infection in patients with healthy immune systems, but is one of the leading causes of morbidity and mortality in immunocompromised people, such as patients recovering from organ transplantation and people fighting HIV infection, cancer, and malnutrition (Stringer et al., Emerging Infectious Disease, 8(9), 897-896 (2002)). Indeed, Pneumocystis pneumonia is the most common AIDS-defining opportunistic infection, and has been observed in patients suffering from even mild forms of immunodeficiency (Stringer et al., supra).
  • Pneumocystis pneumonia The clinical presentation of Pneumocystis pneumonia consists of malaise, fever, dry cough, exercise-induced dyspnoea, weight loss, and pulmonary infiltrates (see, e.g., Choiaid et al., Eur. Respir. J., 8, 1554-1558 (1995)).
  • Pneumocystis pneumonia is caused by infection of Pneumocystis jiroveci (previously named Pneumocystis carinii), which has been categorized both as a fungus and a parasite.
  • Pneumocystis pneumonia remains a common AIDS-defining illness.
  • Current therapy for Pneumocystis pneumonia focuses on eradicating the fungus, and treatment often is limited by adverse side effects in the patient.
  • Side effects of a popular Pneumocystis pneumonia treatment, trimethoprim and sulfamethoxazole (TMP-SMX) include vomiting, bone marrow suppression, and hepatitis (Wilkin and Feinberg, Am. Fam. Physician, 60, 1699-1714 (1999)).
  • TMP-SMX trimethoprim and sulfamethoxazole
  • Other therapeutic modalities can result in deleterious hyperpulmonary inflammatory responses, such as lung damage associated with destroying the fungal organisms and recovery of the immune response.
  • TMP-SMX has been questioned where, for example, HIV burden is high and/or strict compliance with drug therapy is problematic (see, e.g., Madhi et al., Clin. Infect. Dis., 35, 1120-26 (2002)).
  • the invention provides a method of identifying or characterizing an agent that modulates Pneumocystis pneumonia.
  • the method comprises (a) administering the agent to an interleukin 21 receptor (IL-21 R) 7' knockout non-human mammalian model, and (b) determining the effect of the agent on Pneumocystis pneumonia in the IL-21R "7" knockout non-human mammalian model.
  • the invention further provides a method for the prophylaxis or treatment of Pneumocystis pneumonia in a mammal.
  • the method comprises administering to the mammal a therapeutically effective amount of an IL-21 polypeptide, an IL-21 polypeptide variant, a biologically-active fragment of either of the foregoing, or a nucleic acid encoding any of the foregoing.
  • the invention is predicated, in part, on the surprising discovery that interleukin-21 (IL-21) modulates the onset of pneumonia caused by Pneumocystis jiroveci.
  • IL-21 is a cytokine produced by CD4 + T cells that is structurally related to IL-2, IL-4, and IL- 15 (Parrish-Novak et al., Nature, 408, 57-63 (2000)).
  • IL-21 acts synergistically on T cells with a proliferative signal provided by anti-CD3 antibodies, and promotes expansion of mature B cells in response to stimulation through CD40.
  • IL-21 in synergy with Flt3 ligand and IL- 15, promotes expansion and differentiation of NK cells from bone marrow progenitors in vitro, and enhances lytic effector function against target cells in lysis assays (Parrish- Novak et al. (2000), supra).
  • the invention provides materials and methods for studying Pneumocystis pneumonia and characterizing agents that modulate Pneumocystis infections, Pneumocystis pneumonia, and other inflammatory lung diseases using animal models having modified IL-21 functions.
  • the invention further provides a method for treating or preventing Pneumocystis pneumonia in a mammal.
  • the invention provides a method of identifying or characterizing an agent that modulates Pneumocystis pneumonia.
  • the method comprises (a) administering the agent to an interleukin 21 receptor (IL-21 R) "7" knockout non-human mammalian model, and (b) determining the effect of the agent on Pneumocystis pneumonia in the IL-21R "7" knockout non-human mammalian model.
  • the IL-21R is a type I cytokine receptor expressed by, for example, CD23 + B-cells, B-cell lines, a T-cell leukemia line, and NK-cell lines.
  • the protein comprises 538 amino acids and contains a WSXWS (SEQ ID NO: 1) motif in the extracellular region.
  • the human IL-21R gene is located on chromosome 16pl2 (see, e.g., Parrish-Novak et al. (2000), supra; Ozaki et al., Proc. Natl. Acad. ScL USA, 97, 11439-44 (2000)).
  • the IL-21R forms heterodimers with the common cytokine receptor gamma ( ⁇ c ) chain, also found in receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 (Leonard, Nat. Rev. Immunol, 1(3), 200-208 (2001); Asao et al., /. Immunol, 167, 1-5 (2001)).
  • the functional signaling complex activates Janus kinase (Jakl, Jak3) and Stat proteins (see, e.g., Asao et al., /. Immunol, 167, 1-5 (2000)).
  • the sequence of the human IL-21R is available as GENB ANK® Accession Nos. NM_021798 (GI:31083186), NM_181079 (GI:31083179), and NM_181078 (GL31083173).
  • a human ⁇ c sequence is available as GENBANK® Accession No. NM_000206 (GL4557881).
  • the mouse ⁇ c sequence is available as GENBANK® Accession No. NM_021887 (GI: 11230785).
  • the amino acid sequence of human IL-21R precursor is disclosed at, for example, GENBANK® Accession No. NP_851565 (GL31083180).
  • the amino acid sequence of the mouse IL-21R is disclosed at, for example, GENBANK® Accession No. NP_068687 (GI: 11230786).
  • the method of the invention comprises administering an agent to an IL-2 IR "7" knockout non-human mammalian model.
  • "Knock out” animal models are well known in the art, and any non-human mammal is appropriate for use in the inventive method.
  • suitable non-human mammals include, but are not limited to, mice, rats, guinea pigs, hamsters, rabbits, dogs, cats, pigs, cows, horses, sheep, goats, bears, tigers, lions, and primates (e.g., chimpanzees and monkeys).
  • Specific gene functions can be disrupted by deleting all or part of a gene or replacing the gene with other sequences to generate a null allele.
  • Homozygous knock out animals lacking a gene of interest can be generated by, for example, cross-breeding mammals having a null allele.
  • the somatic and germ cells of the non-human mammalian model comprise a disrupted IL-2 IR gene, the disruption being sufficient to diminish or inhibit the binding of IL-21 to the cell surface and/or block signaling through the IL-21 signal transduction pathway.
  • the IL-21R gene can be disrupted to destroy the IL-21 ligand binding site expressed at the cell surface.
  • the IL-21R gene can be modified to abolish intracellular signaling associated with IL-21/IL-21R interactions.
  • the IL-21R gene can be modified to prevent or impair transcription and/or translation and/or incorporation of the IL-21 R on the cell surface.
  • Gene disruption or deletion is often obtained via homologous recombination between host cell DNA and a targeting DNA vector introduced into a host cell via calcium phosphate/DNA co-precipitates, microinjection of DNA into the nucleus, electroporation, bacterial protoplast fusion with intact cells, transfection, polycations, and the like (see, for example, Keown et al., Meth. Enzym., 185, 527-537 (1990); Mansour et al., Nature, 336, 348- 352 (1988)).
  • IL-21R "7" knockout mice are further described in, for example, Ozaki et al., Science, 298, 1630-1634 (2002) and U.S. Patent Application Publication No. 2005/0193434 (Leonard et al.).
  • the inventive method can be used to identify or characterize an agent that modulates Pneumocystis pneumonia.
  • modulates is meant the agent prevents, in whole or in part, or treats, in whole or in part, Pneumocystis pneumonia.
  • the method can be utilized to identify an agent that reduces the severity of one or more symptoms of Pneumocystis pneumonia or reduces the severity of the illness, itself.
  • the IL- 21 R ⁇ ' ⁇ knockout non-human mammalian model can be infected with Pneumocystis.
  • the IL-21 R ⁇ A knockout non-human model further exhibits symptoms of Pneumocystis pneumonia such as, for instance, malaise, fever, dry cough, weight loss, pulmonary infiltrates, exudate production in alveolar spaces, interstial thickening, and/or extensive lung damage from fibrosis.
  • Microscopic identification of Pneumocystis organisms can be performed using, e.g., Giemsa nuclear stains or silver stains (such as Gomori's methenamine silver nitrate method) that reveal cyst walls or polychrome methylene blue that reveals intracystic sporozoites.
  • the agent of the inventive method can comprise any biologically acceptable material suitable for administration in vivo.
  • the agent can be a nucleic acid, peptide, small molecule, pharmaceutical candidate, plant extract, chemical compound (e.g., an organic moiety or inorganic moiety), and the like.
  • the agent can be isolated from a natural source or generated synthetically.
  • small molecule is meant a compound comprising a single structural and functional unit or a small number of simple structural units (e.g., less than about 1000 Daltons), as distinguished from macromolecules comprising a large string of several simple structural units.
  • the agent can be a member of compound libraries produced by combinatorial chemistry.
  • agents identified by the assay can be further characterized if, for example, they mediate a statistically meaningful change in the onset or progression of Pneumocystis pneumonia compared to matched IL-21R "7" knockout non-human mammalian models not treated with the agent. For example, a student's T-test can be used to compare the values obtained in the assay with the control values.
  • an IL-21/IL-21R antagonist to the IL-21R "7" knockout non-human mammalian model.
  • An "antagonist” is an agent that inhibits activity of a cell receptor normally stimulated by a naturally occurring substance. Accordingly, an IL-21/IL-21R antagonist binds to IL-21 or to the IL-21R and inhibits binding of IL-21 to the IL-21 R and/or inhibits an activity normally induced by binding of IL-21 with its receptor, as described in, e.g., U.S. Patent Application Publication No. 2005/0193434.
  • an IL-21/IL-21R antagonist can bind to IL-21 or to the IL- 21R and diminish or prevent binding of IL-21 to the IL-21R.
  • an IL-21/IL-21R antagonist can bind to the IL-21 R and diminish or prevent downstream signaling that would normally be induced by IL-21 binding, such as activation of the Jak/Stat intracellular signaling pathway.
  • Suitable antagonists, as well as suitable agonists described below, include, e.g., a variety of classes of molecules including peptides, such as ligand-like polypeptides, antibodies, fusion polypeptides, and fragments or subsequences thereof, chemical compounds, small molecules, and the like.
  • Exemplary antagonists include: neutralizing antibodies specific for IL-21 or the IL-21 R, soluble IL-21 R molecules, and IL- 21R fusion proteins, such as IL-21 R-immunoglobulin Fc molecules. Exemplary antagonists are further described in, e.g., U.S. Patent Application Publication Nos. 2002/0128446, 2003/0125524, and 2003/0108549.
  • the method of the invention further comprises determining the effect of the agent on Pneumocystis pneumonia in the IL-21R "7" knockout non-human mammalian model.
  • the technique for determining (or observing) the effect of the agent on the onset or progression of Pneumocystis pneumonia will depend on the particular IL-21 R "7" knockout non-human mammalian model selected.
  • Fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) are "gold standards" for detecting Pneumocystis infection in humans, and may be appropriate for use in certain animal models (see Cruciani et al, Chronic Infect. Dis., 36, 936-937 (2003)).
  • procedures involving cytologic examination of nasopharyngeal aspirates or sputum also can detect Pneumocystis infection and the progression of pneumonia.
  • chest radiographs and high-resolution computed tomography can be used to observe the morphological changes of lung tissue.
  • HRCT high-resolution computed tomography
  • the invention further provides a method for the prophylaxis or treatment of Pneumocystis pneumonia in a mammal.
  • prophylaxis is meant prevention or inhibition of the onset of Pneumocystis pneumonia.
  • Prophylaxis in the context of the invention, also can encompass slowing of the onset of Pneumocystic pneumonia, which does not involve complete prevention of the illness or symptoms associated therewith.
  • treatment is meant the alleviation, in whole or in part, of Pneumocystis pneumonia, i.e., a reduction of the severity of the illness.
  • the inventive method results in amelioration of one or more symptoms associated with Pneumocystis infection and pneumonia resulting therefrom.
  • the method comprises administering to the mammal a therapeutically effective amount of an IL-21 agonist.
  • the IL-21 cytokine was cloned from a cDNA library derived from activated CD3+ T-cells (Parrish-Novak et al. (2000), supra).
  • IL-21 cDNA encodes a secreted protein of 131 amino acids closely related to IL-2 and IL-15.
  • the IL-21 gene has been mapped to human chromosome 4q26-q27 near the IL-2 gene.
  • a nucleic acid sequence and polypeptide sequence for murine IL-21 are disclosed as GENB ANK® Accession No. NM_021782 (GI: 11140820) and GENB ANK® Accession No.
  • AF254070 (GI: 11093537).
  • a nucleic acid and polypeptide sequence of human IL-21 are disclosed as GENB ANK® Accession No. NM_021803 (GI: 11141874) and GENB ANK® Accession No. AF254069 (GI: 11093535) (see U.S. Patent Application Publication No. 2005/0193434).
  • the amino acid sequences of human IL-21 and murine IL-21 also are described in U.S. Patent Application Publication 2006/0057123.
  • a clone containing all or most of the IL-21 sequence (designated HTGED19) was deposited with the American Type Culture Collection ("ATCC”) on Mar.
  • ATCC American Type Culture Collection
  • Porcine IL-21 is described in, for example, Muneta et al., /. Vet. Med. ScL, 66(3), 269-75 (2004).
  • IL-21 mRNA is expressed in activated CD4+ cells, but not in other T cells, B- cells, or monocytes (Parrish-Novak et al. (2000), supra). However, IL-21 stimulates proliferation of B-cells that are stimulated by cross-linking of the CD40 antigen and proliferation of B cells stimulated by IL-4 in addition to anti-IgM. IL-21 also stimulates proliferation of naive (CD45RA(+)) cells, mediated by engagement of CD3. In addition, IL- 21 has been shown to stimulate the proliferation of bone marrow progenitor cells and to enhance the expression of the NK-cell marker CD56 in the presence of IL- 15 (see Pelletier et al., /.
  • An "agonist” refers to any agent that provides for increased IL-21 activity in the mammal.
  • An IL-21 agonist can establish IL-21 activity in a host lacking IL-21 activity (such as an IL-2 Y 1' knockout non-human mammalian model) or can enhance IL-21 activity in a host displaying endogenous IL-21 activity.
  • an IL-21 agonist can have affinity for the IL-21R and stimulate an activity (e.g., a cellular and/or immune response) induced by the binding of IL-21 with its receptor, such as the IL-21 functions described above.
  • an IL-21 agonist is a molecule that binds to the IL-21 receptor and induces intracellular signaling via the Jak/Stat signaling pathway.
  • IL-21 agonists include, for example, an IL-21 polypeptide, an IL-21 polypeptide variant, or a fragment of either of the foregoing; an IL-21 mimetic; a ligand (e.g., all or part of an antibody) that binds IL-21R and triggers signal transduction; a nucleic acid encoding IL-21 or an IL-21 peptide variant; a nucleic acid encoding a biologic ally- active fragment of IL-21; and a nucleic acid encoding a peptide that displays IL-21 activity.
  • IL-21 agonists are further described in, for example, U.S. Patent Application Publication 2005/0193434.
  • the IL-21 agonist is an IL-21 polypeptide, an IL-21 polypeptide variant, or a biologically-active fragment of any of the foregoing.
  • the term "IL-21 polypeptide” is meant to encompass an IL-21 oligopeptide, peptide, polypeptide, or protein sequence, and fragments or portions thereof.
  • the IL-21 polypeptide can be naturally occurring, e.g., isolated from a natural source, or can be generated synthetically. In this regard, the IL-21 polypeptide can be generated using the amino acid and nucleotide sequences of human IL-21 disclosed as GENB ANK® Accession Nos.
  • AAG29348 (GI: 11093536) and AF254069 (GI: 11093535), respectively, or the amino acid and nucleotide sequences of mouse IL-21 designated as GENB ANK® Accession Nos. AAG29349 (GI: 11093538) and AF254070 (GI: 11093537), respectively.
  • a "variant" of a polypeptide refers to an amino acid sequence that is altered by one or more amino acids.
  • the variant can have conservative changes, wherein a substituted amino acid has similar structural or chemical properties, e.g., replacement of leucine with isoleucine.
  • conservative amino acid substitutions can involve exchanging an amino acid within one class of residues for an amino acid residue that belongs to the same class.
  • acidic residues include Asp and GIu; basic residues include Lys, Arg, and His; hydrophilic uncharged residues include Ser, Thr, Asn, and GIn; aliphatic uncharged residues include GIy, Ala, VaI, Leu, and He; non-polar uncharged residues include Cys, Met, and Pro; and aromatic residues include Phe, Tyr, and Trp. More rarely, a variant can have non-conservative changes, such as replacement of an amino acid residue from one class with that from another class (e.g., replacement of a glycine with a tryptophan). Minor variations can also include amino acid deletions or insertions, or both.
  • IL-21 variants or fragments can be screened for any of the IL-21 functions described herein using routine laboratory techniques.
  • the IL-21 polypeptide variant preferably has an amino acid sequence that is at least 50% identical (e.g., 50% identical, 60% identical, 65% identical, 70% identical, 80% identical, or 85% identical) to the amino acid sequence of IL- 21. More preferably, the variant has an amino acid sequence that is at least 85% identical (e.g., 85% identical, 90% identical, or 95 % identical) to the amino acid sequence of IL-21. Most preferably, the variant has an amino acid sequence that is greater than 95% identical (e.g., 99% identity) to the amino acid sequence of IL-21.
  • Identity with respect to amino acid or polynucleotide sequences refers to the percentage of residues or bases that are identical in the two sequences when the sequences are optimally aligned.
  • the “optimal alignment” is the alignment which provides the highest identity between the aligned sequences. Alignment techniques and bioinformatics methods are further described in U.S. Patent Application Publication 2005/0193434 and International Patent Application Publication WO 02/083851.
  • the IL-21 agonist alternatively can comprise a fragment of an IL-21 polypeptide or IL-21 variant.
  • Amino acid sequence fragments or portions thereof can be from about 5 to about 30 amino acids, and preferably from about 5 to about 15 amino acids in length. Such fragments and portions desirably retain the biological activity or function of the IL-21 polypeptide.
  • the IL-21 fragment contains the IL-21R binding site, such that the IL-21 fragment interacts with the IL-21R to trigger intracellular signaling.
  • the IL-21 polypeptide, IL-21 variant, or fragment of any of the foregoing also can have one or more post-translational modifications, such as, but not limited to, glycosylation, acetylation, acylation, ADP-ribosylation, methylation, phosphorylation, carboxylation, esterification, myristoylation, and amidation (Proteins - Structure and Molecular Properties, 2nd Ed., Creighton, W. H. Freeman and Company, New York (1993); Posttranslational Covalent Modification Of Proteins, B. C. Johnson, Ed., Academic Press, New York, 1-12 (1983)).
  • post-translational modifications such as, but not limited to, glycosylation, acetylation, acylation, ADP-ribosylation, methylation, phosphorylation, carboxylation, esterification, myristoylation, and amidation
  • Candidate IL-21 variants or fragments can be screened for any of the IL-21 functions described herein (e.g., stimulation of B-cell, bone marrow progenitor cell, or (CD45RA(+)) cell proliferation) using routine laboratory techniques (such as, for example, the methods described in Pelletier et al, supra; Leonard et al. (2005), supra; and Ettinger et al., /. Immunol, 175, 7867-7879 (2005)).
  • routine laboratory techniques such as, for example, the methods described in Pelletier et al, supra; Leonard et al. (2005), supra; and Ettinger et al., /. Immunol, 175, 7867-7879 (2005).
  • IL-21 polypeptides such as IL-21 polypeptides
  • a nucleic acid encoding IL-21 can be expressed in either prokaryote or, preferably, eukaryote cell culture to obtain large amounts of polypeptide.
  • Hosts can include microbial, yeast, insect, and mammalian cell cultures.
  • Isolation and purification of IL-21 polypeptide from mixed source material can be carried out by conventional means including preparative chromatography, affinity column chromatography, and immunological separations involving monoclonal or polyclonal antibodies, as further described in U.S. Patent Application Publication No. 2006/0057123.
  • the IL-21 agonist is a nucleic acid encoding an IL-21 polypeptide, an IL-21 polypeptide variant, or a biologic ally- active fragment of either of the foregoing.
  • nucleic acid refers to any oligonucleotide or nucleotide sequence, fragments or portions of either of the foregoing, which encode all or part of IL-21 or a variant thereof.
  • the nucleic acid molecule or polynucleotide can be DNA or RNA of either genomic or synthetic origin, which can be single- or double- stranded, and can be a coding (sense) or non-coding (anti-sense) strand.
  • a nucleic acid encoding IL-21, encoding an IL-21 polypeptide variant, or encoding a biologically-active fragment of IL-21 can be composed of unmodified RNA or DNA or modified RNA or DNA.
  • the nucleic acid encoding IL-21 can contain one or more modified bases or modified internucleotide linkages, wherein the modifications increase the stability of the polynucleotide or improve the polynucleotides in some other manner.
  • “Modified" bases include, for example, tritylated bases and unusual bases, such as inosine.
  • a variety of modifications can be made to DNA and RNA; thus, "nucleic acid” embraces chemically, enzymatically, or metabolically modified forms.
  • the nucleic acid of the inventive method can comprise the full-length IL-21 cDNA sequence.
  • a nucleic acid encoding an IL-21 polypeptide also can contain intronic sequences, 5' and/or 3' untranslated sequences, the coding region, the signal sequence, the secreted protein coding region, or any combination of the foregoing. Fragments, epitopes, domains, degenerate sequences, and variants of the IL-21 polynucleotide also are suitable.
  • Fragments include, but are not limited to, nucleic acid sequences that are greater than 10-60 nucleotides in length, and preferably include fragments that are at least 61-100 nucleotides, or which are 101 nucleotides or greater in length.
  • the nucleic acid alternatively can encode an IL-21 polypeptide variant whereby the nucleic acid sequence comprises deletions, insertions, and/or substitutions of different nucleotides, compared with the nucleic acid sequence of native IL-21, which results in a polynucleotide that encodes a functionally equivalent IL-21 polypeptide.
  • Altered nucleic acid sequences can further include polymorphisms of the polynucleotide encoding the IL-21 polypeptide.
  • the encoded IL-21 variant protein also can comprise deletions, insertions, or substitutions of amino acid residues, which produce a silent change and result in a functionally equivalent IL-21 protein. Deliberate amino acid substitutions can be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues, as long as the biological activity of IL-21 protein is retained.
  • negatively charged amino acids can include aspartic acid and glutamic acid; positively charged amino acids can include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values can include leucine, isoleucine, and valine; glycine and alanine; asparagine and glutamine; serine and threonine; and phenylalanine and tyrosine.
  • One or more nucleic acids encoding an IL-21 polypeptide, an IL-21 polypeptide variant, or a biologically-active fragment of either of the foregoing, can be incorporated into an expression vector to enhance uptake of the nucleic acid into host cells.
  • suitable expression vectors include, for instance, plasmids, plasmid-liposome complexes, and viral vectors, e.g., parvoviral-based vectors (i.e., adeno-associated virus (AAV)-based vectors), retroviral vectors, herpes simplex virus (HSV)-based vectors, AAV- adenoviral chimeric vectors, and adenovirus-based vectors.
  • the nucleic acid is operably linked to regulatory sequences necessary for expression, e.g., a promoter that directs transcription of the nucleic acid in a eukaryotic (desirably mammalian) cell (see, for example, U.S.
  • the IL-21 agonist can comprise all or part of an antibody that interacts with the IL-21R to trigger intracellular signaling associated with IL-21 biological activity.
  • a naturally occurring antibody e.g., IgG
  • IgG includes four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • the biological activity of IL-21 can be mimicked using fragments of a naturally occurring antibody.
  • antibody fragments that can be used in the context of the invention include, but are not limited to, (i) an Fab fragment consisting of the VL, VH, CL and CHl domains; (ii) an Fd fragment consisting of the VH and CHl domains; (iii) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (iv) a dAb fragment (Ward et al., Nature, 341, 544-546 (1989)) which consists of a VH domain; (v) an isolated complimentarily determining region (CDR); and (vi) an F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region.
  • bispecific antibodies can be used in the context of the invention. Bispecific antibodies can be generated in a number of ways, such as chemical cross-linking of two IgG molecules or two Fab or Fab' fragments and by fusion of two hybridomas.
  • An exemplary bispecific antibody comprises an Fab that binds to an IL-21 R and another Fab that binds to the common cytokine receptor ⁇ c chain.
  • Diabodies, recombinant bispecific antibodies constructed from heterogeneous single-chain antibodies, also are appropriate for use in the invention (see, for example, Kontermann, Acta Pharmacologica Sinica, 26(1), 1-9 (2005); Takemura et al., Protein Engineering Design and Selection, 13(S), 583-88 (2000)).
  • the antibody or fragment thereof specifically binds or specifically immunoreacts with the IL-21R.
  • the antibody binding is non-random, and the antibody differentially (or preferentially) binds the IL-21R compared to an unrelated biological moiety.
  • the antibody or fragment thereof (or any other IL-21 mimetic) interacts with the IL-21R in such a manner as to trigger the intracellular signaling cascade responsible for IL-21 activity.
  • the Janus Activated kinase (Jak)/Signal Transducer and Activator of Transcription (Stat) pathway is triggered upon interaction with the IL-21R.
  • Jaks spurs tyrosine phosphorylation of cellular substrates, including the Jak-associated cytokine receptor chains.
  • Jakl and Jak3 are activated, which results in phosphorylation of one of the IL-21R chains.
  • the phosphorylated tyrosines serve as docking sites for Stat proteins, which also are phosphorylated.
  • the Stat proteins dimerize and translocate to the nucleus to become high-affinity transcription factors.
  • the signaling pathway activated by IL-21/IL-21R interaction is further described in Leonard, Nature Reviews, 1, 200-208 (2001) and U.S. Patent Application Publication 2005/0193434.
  • the invention provides a method for the prophylaxis or therapy of Pneumocystis pneumonia in a mammal.
  • Pneumocystis infection has been observed in, for example, rats, rabbits, mice, dogs, sheep, goats, ferrets, chimpanzees, guinea pigs, horses, and monkeys across the globe.
  • the methods disclosed herein have equal application in medical and veterinary settings, and the term "mammal" as used herein encompasses both human and non- human mammals.
  • the mammal is a human.
  • the IL-21 agonist (or multiple IL-21 agonists) can be delivered to the mammal via any desired route of administration so long as Pneumocystis pneumonia is treated or prevented in the mammal.
  • the IL-21 agonist can be modified and incorporated into a physiologically-acceptable formulation to maximize efficacy of the inventive method.
  • peptides in general including IL-21 peptides and fragments or variants thereof, can be susceptible to hydrolysis of amide bonds (e.g., catalyzed by peptidases) and disruption of essential disulfide bonds or formation of inactivating or unwanted disulfide linkages (Carone et al., /. Lab. Clin. Med., 100, 1-14 (1982)).
  • IL-21 agonist e.g., IL-21 polypeptide, IL-21 variant thereof, or fragment of either of the foregoing or a nucleic acid encoding any of the foregoing
  • routes of delivery include oral, intravenous, intraarterial, intrathecal, intramuscular, subcutaneous, intraperitoneal, intratracheal, topical, mucosal, intracisternal, buccal, rectal, nasal, pulmonary, transdermal, vaginal, ocular, and the like.
  • the IL-21 agonist is preferably delivered intranasally, intratracheally, by inhalation, or parenterally via, e.g., intravenous infusion.
  • a DNA sequence encoding an IL-21 peptide, IL-21 variant, or fragment of either of the foregoing can be inserted ex vivo into mammalian cells previously removed from a given animal, in particular a human, host. Such cells can be employed to express the encoded peptide in vivo after introduction into the host.
  • nucleic acids can be inserted into cells directly in vivo, such as by use of an appropriate non- viral or viral vector.
  • Cells transfected in vivo are expected to produce effective amounts of IL-21 agonist, e.g., IL-21 peptide, directly in vivo.
  • aerosol delivery of nucleic acids encapsulated in cationic liposomes results in transfection and protein production in airway epithelia and alveolar lining cells (Stribling et al., Proc. Natl. Acad. Sci USA, 89, 11277-11281 (1992)).
  • the IL-21 agonist is administered in a physiologically-acceptable (e.g., pharmaceutically-acceptable) composition.
  • a composition comprising an IL-21 agonist can be combined with various carriers, adjuvants, diluents or other therapeutics, if desired.
  • Pharmaceutically acceptable carriers useful with the methods described herein are conventional. Remington's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, Pa., 15th Edition (1975), describes compositions and formulations suitable for delivery of the IL-21 agonists and cells disclosed herein.
  • compositions include liquid preparations for orifice (e.g., oral, nasal, anal, vaginal, intragastric) administration such as suspensions, syrups or elixirs; and, preparations for parenteral, subcutaneous, intradermal, intramuscular or intravenous administration (e.g., injectable administration, including the use of needleless injectors) such as sterile suspensions or emulsions, are provided.
  • orifice e.g., oral, nasal, anal, vaginal, intragastric
  • parenteral, subcutaneous, intradermal, intramuscular or intravenous administration e.g., injectable administration, including the use of needleless injectors
  • injectable administration including the use of needleless injectors
  • the IL-21 agonist may be in admixture with a physiologically acceptable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, balanced salt solutions, aqueous dextrose, glycerol, ovalbumin, albumin, globulins, or the like.
  • a physiologically acceptable carrier diluent, or excipient
  • conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
  • the IL-21 agonist can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, sodium acetate or sorbitan monolaurate, preservatives, adjuvants, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and pH buffering agents and the like, depending upon the route of administration and the preparation desired.
  • auxiliary substances such as wetting or emulsifying agents, sodium acetate or sorbitan monolaurate, preservatives, adjuvants, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and pH buffering agents and the like, depending upon the route of administration and the preparation desired.
  • preservatives such as sodium acetate or sorbitan monolaurate, preservatives, adjuvants, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and pH buffering agents and the like, depending upon the route of administration and the preparation desired
  • a physiologically-acceptable composition comprising an IL-21 agonist can comprise additional therapeutic agents.
  • additional therapeutics include other an ⁇ -Pneumocystis agents, antiviral compounds, virucides, fungicides, immunomodulators, antibiotics, and absorption enhancers.
  • compositions comprising an IL-21 agonist, such as an IL-21 peptide, fragment or variant thereof, required to treat or prevent Pneumocystic pneumonia in a mammal are dependent on numerous factors, such as size of the animal, the duration of the illness, the presence or absence of other infections, interindividual differences in pharmacokinetics, drug distribution, metabolism, and the like.
  • the amount of composition administered should be sufficient to reduce the level of Pneumocystis infection, reduce the severity of Pneumocystis pneumonia symptoms, suspend further damage of lung tissue caused by Pneumocystis pneumonia, affect the production of immunoglobulins induced by IL-21, or any other desired biological response to treatment.
  • the amount of IL-21 agonist (or multiple IL-21 agonists) in a particular composition required to achieve a desired biological response can be determined using routine methods in the art, such as the methods described herein for detecting Pneumocystis infection, Pneumocystic pneumonia, and lung damage resulting therefrom.
  • the dose administered should be an amount necessary to achieve an "effective level" in the individual mammal, i.e., a level of IL-21 agonist sufficient to achieve the desired biological response in the individual mammal.
  • the "effective level” can be defined, for example, using the IL-21 R "7" knockout non-human mammalian models described herein.
  • in vitro assays can aid in determining an effective level of IL- 21 agonist.
  • Ettinger et al., supra describes methods of analyzing the biological activity of IL-21.
  • An exemplary method entails isolating B cells obtained from patient peripheral blood and culturing the cells with varying levels of IL-21.
  • Flow cytometry analysis can reveal the level of IL-21 providing optimal biological activity, e.g., IL-21 induced differentiation of plasma cells (see Ettinger et al., supra).
  • the dose administered to a mammal can be, for example, about 1 mg of agonist (preferably IL-21 )/kg of patient to about 6 mg of agonist/kg of patient (e.g., about 1.5 mg of agonist/kg of patient , 2 mg of agonist/kg of patient, 2.5 mg of agonist/kg of patient, 3 mg of agonist/kg of patient, 3.5 mg of agonist/kg of patient, 4 mg of agonist/kg of patient, 4.5 mg of agonist/kg of patient, 5 mg of agonist/kg of patient, 5.5 mg of agonist/kg of patient, or 6 mg of agonist/kg of patient).
  • agonist preferably IL-21
  • Suitable doses and dosage regimens involving nucleic acid administration also can be determined by conventional range-finding techniques known to those of ordinary skill in the art, and will depend on the particular method of delivery and expression vector used. For example, if the nucleic acid is inserted into a viral vector, preferably about 10 6 viral particles to about 10 12 viral particles (including all integers within the range of about 10 6 viral particles to about 10 12 particles) are delivered to the mammal. If the nucleic acid is incorporated into a plasmid, preferably at least about 1 ⁇ g, more preferably at least about 100 ⁇ g, and even more preferably at least about 1 mg of DNA is administered. Of course, other routes of administration may require smaller or larger doses to achieve a therapeutic effect. DNA can be administered through any appropriate route of administration, including the exemplary routes of administrated detailed herein. Any necessary variations in dosages and routes of administration can be determined by the ordinarily skilled artisan using routine techniques known in the art.
  • An effective amount of an IL-21 agonist can be administered in a single dose, or in several doses, for example daily, during a course of treatment. Treatment progress can be evaluated using any suitable method, including those methods described herein.
  • Fiberoptic bronchoscopy and bronchoalveolar lavage are useful for detecting Pneumocystis infection (Cruciani et al, Chronic Infect. Dis., 36, 936-937 (2003)).
  • the "induced sputum" technique and procedures involving cytologic examination of nasopharyngeal aspirates are less invasive than BAL and less sensitive, but also are 100% specific (Chouaid et al., supra).
  • Pneumocystis organisms can be detected microscopically, and chest radiographs and high-resolution computed tomography (HRCT) can be used to view Pneumocystis cysts, interstitial fibrosis, and honeycombing of lung tissue in live subjects.
  • HRCT computed tomography
  • Techniques for detecting and quantifying Pneumocystis infection are known in the art and further described in, for example, Lu et al., /. Clin. Microbiol, 33, 2785-2788 (1995); Helweg-Larsen et al., BMC Infectious Diseases, 2(28) (2002) (http://www.biomedcentral.eom/1471-2334/2/28); and Chouaid et al., supra.
  • This example demonstrates a method of generating an IL-21 R knock out non- human mammalian animal model.
  • a method of generating an IL-21R knock out mouse model is described in U.S. Patent Application Publication No. 2005/0193434 (Leonard et al.).
  • a DNA construct was designed to eliminate the extracellular domain of the IL-21 receptor.
  • Murine IL-21 receptor (IL-21R) cDNAs containing all IL-21R coding exons were identified in a bacterial artificial chromosome (BAC) clone library prepared from 129Sv mice (Genome Systems).
  • BAC bacterial artificial chromosome
  • a targeting construct was designed delete the IL-21R coding region spanning from the signal peptide to the transmembrane domain, and frame shift the residual portion of the cytoplasmic domain of the receptor.
  • the targeting construct has 4-kb (Bam HI/Eco RI) and 2-kb (Xho I/Nhe I) 5' and 3' flanking fragments, and is illustrated in Figure IA of U.S. Patent Application Publication No. 2005/0193434.
  • the targeting DNA construct was introduced into embryonic stem cells, which, in turn, were injected into C57BL/6 blastocysts. The resulting chimeric mice were mated with C57BL/6 mice, and the resulting heterozygous offspring were interbred. [0041] Following interbreeding, genetic analysis confirmed loss of IL-21R.
  • This example provided a method of generating an IL-21 R "7" knockout non-human mammalian model suitable for use in the inventive method.
  • Wild type Balb/c mice or IL-21R »- " /- " knock out Balb/c mice were sensitized by administration of 100 ⁇ g ovalbumin (OVA) (Grade V, Sigma) emulsified in a 200 ⁇ l intraperitoneal (i.p.) injection with an equal volume mixture of alum (Pierce Laboratories, Rockford, IL). The injections were administered on day 0 and day 5. The mice were challenged with 50 ⁇ g OVA intratracheally on day 14 and an additional 50 ⁇ g OVA intranasally on day 15. Control mice were sensitized and challenged with phosphate-buffered saline (PBS).
  • PBS phosphate-buffered saline
  • IL-21R "7" knock out mice administered OVA for sensitization contained focal infiltrates in the lungs, indicating pulmonary inflammation. Further evaluation revealed that naive IL-21R “7” knock out mice (i.e., knock out mice not administered OVA) also suffered from focal infiltrates (7/8 mice examined at 10 weeks or greater). The infiltrates contained Pneumocystis organisms as detected by Periodic Acid Schiff (PAS) staining and verified by silver stain.
  • PES Periodic Acid Schiff
  • the IL-21R "7" knockout non-human mammalian model of the inventive method is susceptible to Pneumocystis infection and, therefore, useful as a tool for characterizing agents that modulate Pneumocystis pneumonia.

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Abstract

L'invention concerne un procédé d'identification ou de caractérisation d'un agent qui module la pneumonie interstitielle à Pneumocystis carinii. Le procédé comprend (a) l'administration de l'agent à un modèle mammifère non humain knockout pour le récepteur de l'interleukine 21 (IL-21R)-/-, et (b) la détermination de l'effet de l'agent sur la pneumonie interstitielle à Pneumocystis carinii dans le modèle mammifère non humain knockout IL-21R-/-. L'invention concerne en outre un procédé de prévention ou de traitement de la pneumonie interstitielle à Pneumocystis carinii chez un mammifère. Ce procédé comprend l'administration au mammifère d'une quantité thérapeutiquement efficace d'un polypeptide d'IL-21, d'un variant de polypeptide d'IL-21, d'un fragment biologiquement actif de l'un ou l'autre des précédents, ou d'un acide nucléique codant pour l'un quelconque des précédents.
PCT/US2007/066925 2006-04-21 2007-04-19 Matériaux et procédés de traitement de la pneumonie interstitielle à pneumocystis carinii WO2007130785A2 (fr)

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WO2004003156A2 (fr) * 2002-07-01 2004-01-08 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Le l-21, regulateur de la production d'immunoglobine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004003156A2 (fr) * 2002-07-01 2004-01-08 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Le l-21, regulateur de la production d'immunoglobine

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Title
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MEISSNER N N ET AL: "CD8 T cell-mediated lung damage in response to the extracellular pathogen Pneumocystis is dependent on MHC class I expression by radiation-resistant lung cells" JOURNAL OF IMMUNOLOGY 15 DEC 2005 UNITED STATES, vol. 175, no. 12, 15 December 2005 (2005-12-15), pages 8271-8279, XP002465921 ISSN: 0022-1767 *
OSTIGUY V ET AL: "IL-21 promotes T lymphocyte survival by activating the phosphatidylinositol-3 kinase signaling cascade" JOURNAL OF LEUKOCYTE BIOLOGY 01 SEP 2007 UNITED STATES, vol. 82, no. 3, 1 September 2007 (2007-09-01), pages 645-656, XP008087983 ISSN: 0741-5400 *
PARRISH-NOVAK JULIA ET AL: "Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function" NATURE, NATURE PUBLISHING GROUP, LONDON, GB, vol. 408, no. 6808, 2 November 2000 (2000-11-02), pages 57-63, XP002186602 ISSN: 0028-0836 cited in the application *
WHITE L ET AL: "Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV)" BLOOD 01 MAY 2007 UNITED STATES, vol. 109, no. 9, 1 May 2007 (2007-05-01), pages 3873-3880, XP002465520 ISSN: 0006-4971 0006-4971 *
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